Pharmacokinetics of orally administered pirfenidone in male and female beagles.

Pirfenidone, a promising antifibrotic agent, was administered orally to dogs at 0, 40, 140, and 400 mg/kg/day. Serum was collected for pirfenidone assay at 0, 26 and 39 weeks of treatment. From the pirfenidone concentrations, pharmacokinetic parameters were determined for each dog at each treatment interval. The only significant differences because of gender were for concentration maxima. Unsurprisingly, there were many significant differences because of dose in concentration maximum and area under curve (AUC), and significant, positive linear correlations of both parameters with dose. There were few significant differences in time of maximal concentration and no correlation with dose. The mean +/- SE clearances were 1.99 +/- 0.13, 1.64 +/- 0.13 and 1.78 +/- 0.14 L/h/kg for doses of 40, 140, and 400 mg/kg, respectively, with no significant differences attributable to dose. There was an unexplained pattern in maximal concentration and AUC with regard to duration of treatment, with the parameters being highest at week 0, lowest at week 26, and intermediate at week 39. Clearance had the reverse pattern; time of maximal concentration had no pattern.

Mixed ruminal microbes of cattle produce isopropanol in the presence of acetone but not 3-D-hydroxybutyrate.

The objective was to evaluate the ability of mixed rumen microbes to synthesize isopropanol from acetone or 3-D-hydroxybutyrate. Rumen fluid from seven mature, nonpregnant, dry Holstein cows was incubated with starch or cellulose and additions of acetone, 3-D-hydroxybutyrate, or saline. Rumen fluid was analyzed for isopropanol after 0, 3, 6, and 9 h. No isopropanol was present in any sample at 0 h, and none was present in incubations containing saline or 3-D-hydroxybutyrate at any subsequent time. Incubations that included acetone produced small amounts of isopropanol from 0 to 3 and 3 to 6 h and significantly larger amounts from 6 to 9 h. With starch as the energy substrate, production from 6 to 9 h was 3.8 micromol/min per liter of rumen fluid and 3.7 micromol/min per liter with cellulose as the energy substrate; however, these values did not differ significantly. Mixed rumen microbes could synthesize isopropanol from acetone but not from 3-D-hydroxybutyrate, and rumen microbial metabolism of acetone was the likely source of plasma isopropanol seen in ketotic ruminants.

Bovine ketosis and somatotrophin: risk factors for ketosis and effects of ketosis on health and production.

Aspects of the metabolism and health of 63 cows which had been treated with different amounts of bovine somatotrophin (BST) daily in the preceding lactation and 25 control cows were studied. The aims of the study were first, to identify cows with ketotic conditions, either by measurements of blood metabolite concentrations or by clinical observations, secondly, to evaluate the risk of such conditions in cows treated with BST in the preceding lactation, and thirdly, to examine the metabolic and production consequences of the ketotic conditions in an environment in which the cows' health, body condition and nutrition were closely observed. The cows were categorised objectively by the use of cluster analysis into non-ketotic cows and ketonaemic cows, on the basis of their plasma metabolite concentrations. Twelve of the control cows and none of the cows previously treated with BST were classified as ketonaemic. Similarly, nine of the control cows but only two of the cows previously treated with BST had clinical ketosis. Some, but not all, of the decrease in the risk of clinical ketosis was attributable to the lower body condition score of the cows previously treated with BST. The clinically ketotic cows had a greater risk of other illness in the first 10 days post partum than their herdmates, but the ketonaemic cows had a significantly lower risk of other disease in the first 10 days post partum. The ketonaemic control cows were significantly heavier than the non-ketotic control cows, but they maintained a higher dry matter intake than the latter cows, probably a key factor in reducing the risk of clinical ketosis.

Abomasal interstitial fluid-to-blood concentration gradient of pepsinogen in calves with type-1 and type-2 ostertagiosis.

Pepsinogen and protein concentrations were determined in blood samples, collected from the left gastroepiploic artery and vein, and in abomasal lymph from 15 steers naturally infected with Ostertagia ostertagi and 4 uninfected steers. In steers with type-1 ostertagiosis, the concentration gradient between the mucosal interstitium and the blood alone could account for higher than normal serum pepsinogen concentrations. High interstitial pepsinogen concentrations may have resulted from increased epithelial permeability or increased pepsinogen production and secretion. However, in steers with type-2 ostertagiosis, the concentration gradient could not entirely account for the high serum pepsinogen concentrations, suggesting that capillary permeability or surface area may have been altered. Lymphatic uptake contributed pepsinogen to the blood in all infected steers.

Effects of estrogen on whole animal and tissue glucose use in female and male rainbow trout.

Reports of changes in carbohydrate metabolism during vitellogenesis in fish prompted an investigation of the effects of estrogen on glucose utilization in rainbow trout. Estrogen pellets were implanted in both female and male fish, and a third group of male fish was given a sham operation. After cannulation of the dorsal aorta, D-[1-3H]glucose and 2-deoxy-D-[U-14C]glucose were injected into the fish to observe whole animal and tissue glucose use. We found that estrogen does not affect glucose turnover rate or transit time but causes a decrease in plasma glucose concentration and size of the glucose mixing pool. Adipose tissue in female fish utilized glucose at a higher rate than sham fish. Ovarian tissue used more glucose per kilogram of body weight than the testes of the male fish. Regardless of treatment, brain had the highest rate of glucose consumption per gram of tissue, followed by gonads and red blood cells. Muscle and adipose tissue utilized only small amounts (< 1 nmol.g tissue-1.min-1) of glucose. We conclude that an increase in the rate of whole body glucose use is not responsible for the fall in plasma glucose caused by estrogen and seen during vitellogenesis.

Time series cross-correlation analysis of postparturient relationships among serum metabolites and yield variables in Holstein cows.

Time series cross-correlation analysis was used to determine relationships among serum beta-hydroxybutyrate, glucose, FFA, cholesterol, milk yield, DMI, and estimated net energy balance for 42 d postpartum for 14 multiparous cows. Milk yield was positively associated with beta-hydroxybutyrate concentrations on the same day, and milk yield was a primary determinant of metabolic change. Dry matter intake was negatively correlated with beta-hydroxybutyrate concentrations 3 d later and on the same day. The data supported in vitro studies showing that FFA are positively associated with beta-hydroxybutyrate production, showed that glucose concentrations are negatively cross-correlated with beta-hydroxybutyrate concentrations, and found that estimated net energy balance is negatively cross-correlated with beta-hydroxybutyrate. Analyses suggested that serum glucose and cholesterol concentrations significantly decreased with increased milk yield; analyses also suggested that elevated beta-hydroxybutyrate concentrations were associated with decreases in milk yield 6 d later. beta-Hydroxybutyrate and FFA concentrations 3 to 9 d before parturition were positively related to cholesterol concentrations, and relationships were positive between estimated net energy balance and cholesterol, suggesting that cholesterol concentrations increased as precursors for cholesterol synthesis were available. Time series cross-correlation analysis was a useful tool in examining relationships among variables when repeated samples were obtained from the same individuals.

Impact of bovine somatotropin administration beginning at day 70 of lactation on serum metabolites, milk constituents, and production in cows previously exposed to exogenous somatotropin.

Metabolic and production responses are reported for 72 cows treated with bovine somatotropin (BST) for 30 days starting at day 70 of lactation. Of these 72 cows, 48 had been exposed in the preceding lactation to long-term treatment with BST at 3 dosages and 24 (controls) had not been given BST. Approximately half of the cows in each group were parity-2 cows, the rest were older. Comparisons between groups were made separately for parity-2, and older cows. Analyses, using pretreatment values of each variable as a covariate, indicated that older cows, but not parity-2 cows, significantly (P less than 0.05) increased milk production during treatment. Parity-2 cows, however, had a significantly higher milk fat percentage than controls following treatment. Cows treated with 51.6 or 86 mg BST/d in both parity groups had significantly higher serum-free fatty acids than controls. Estimated net energy balances were significantly lower for older treated cows, but did not significantly differ from controls for parity-2 treated cows. Older cows in the 86 mg of BST/d group tended to have higher concentrations of blood glucose than did older control-group cows. Treatment with BST did not significantly increase serum ketone concentrations in any group of animals, and none of the cows developed clinical ketosis during this period. Estimated net energy balance (ENEB) during treatment was a significant (P less than 0.05) covariate for free fatty acid concentrations in older cows and for milk fat percentage in parity-2 cows. Covariate adjusted analyses, using ENEB during treatment as a covariate, indicated that lipolytic stimuli already acting may be enhanced by treatment with BST, but a negative energy balance was not a necessary precondition for free fatty acid concentrations to increase following somatotropin treatment. Similarly, milk fat percentages for parity-2 treated cows were significantly (P less than 0.05) higher during treatment than controls when ENEB during treatment was used as a covariate. Increased milk fat concentrations in parity-2 treated cows were not associated with significant increases in the ratio of C18:C4-10 milk fatty acids, indicating that increased milk fat resulted from either an increase in incorporation of C18 fatty acids into milk fat coupled with an increase in de novo mammary synthesis of C4-10 milk fatty acids or an increase in C12-16 fatty acids that may arise either from increased tissue mobilization, from diet, or from de novo mammary synthesis.

Dietary protein source (soybean vs. casein) and taurine status affect kinetics of the enterohepatic circulation of taurocholic acid in cats.

The effect of dietary protein source (soybean vs. casein) and taurine status on kinetics of [24-14C] and [taurine-2-3H]taurocholic acid was determined by isotope dilution in 10 adult male cats (six taurine-replete and four taurine-depleted). Taurine-replete cats were fed 1500 mg taurine/kg purified diets containing either 435 g/kg casein (1500 Cas) or soybean protein (1500 Soy) in a crossover design. Taurine-depleted cats were fed the soybean protein diet with no taurine (0 Soy). Specific activity of [14C]- and [3H]taurocholic acid in bile was determined for 6 d following a pulse dose of dual-labeled taurocholic acid. Taurocholic acid pool size was significantly greater in cats when fed the 1500 Soy diet than when fed the 1500 Cas or than in cats fed the 0 Soy diet. Total entry rate, irreversible loss rate and recycling rate of [taurine-2-3H]taurocholic acid and the irreversible loss rate of [24-14C]taurocholic acid tended to be greater in cats when fed the 1500 Soy than the 1500 Cas diet. Irreversible loss rates of taurocholic acid in taurine-replete cats fed the 1500 Soy diet were significantly greater than in taurine-depleted cats, 356 vs. 120 mumol/d [24-14C]taurocholic acid and 445 vs. 56 mumol/d [taurine-2-3H]taurocholic acid. The fraction of taurocholic acid was greater, and the fraction of taurochenodeoxycholic and taurodeoxycholic acids lower in cats when fed the 1500 Soy than when fed the 1500 Cas diet. Taurine-depleted cats had less taurocholic, taurochenodeoxycholic, and taurodeoxycholic acids and greater glycocholic and cholic acids than taurine-replete cats fed the 1500 Soy diet. This study demonstrates that both dietary protein source and taurine status affect taurocholic acid kinetics and bile acid composition in cats.

Bovine somatotropin.

Bovine somatotropin has the potential to alter profoundly the way that dairy herds are managed and to change the ways in which veterinarians provide services to those herds. This article describes the structure, function, and action of somatotropin. The metabolic effects of somatotropin on dairy cattle are discussed.

Postparturient metabolic and production responses in cows previously exposed to long-term treatment with somatotropin.

Postparturient metabolic and production responses were studied for 85 multiparous cows consisting of controls and animals that had been previously exposed to long-term treatment with bST. Older cows previously exposed to bST at high doses (51.6 mg/d) had lower milk yields than controls. However, there were no significant differences compared with controls in milk yield for lower dose (17.2 mg/d) older cows or parity 2 cow groups. The bST-treated groups had higher postpartum DMI, lower serum FFA, lower serum beta-hydroxybutyrate levels, and higher serum glucose than controls. Some bST-exposed groups had lower milk fat but higher milk protein levels. All bST-treated groups had significantly lower ratios of C18 to C4 to 10 milk fatty acids. Control cows of both parity groups were in higher body condition and weighed more than bST-treated cows prior to calving. The differences in postpartum metabolism may be attributed to differences in body composition resulting from bST treatment in the prior lactation, because use of body condition score prior to calving as a covariate did not substantially alter responses. The control cows probably had greater reserves of mobilizable lipid. These contentions are supported by changes in milk composition for bST-treated cows, which were consistent with animals of greater appetite, mobilizing less lipid. The bST-treated cows were probably more energetically efficient milk producers because they produced milk from feed rather than from mobilization of tissue stores. These data suggest that bST use in a prior lactation may have potential benefit in reducing risk of metabolic disorders associated with lipid mobilization in the postparturient period.

Role of eicosanoids in abortion and its prevention by treatment with flunixin meglumine in cows during the first trimester of pregnancy.

Intravenous infusion of E. coli endotoxin at a rate of 4.16 ng/kg/min over 6 hr (total dose 1.5 micrograms/kg) in 5 cows in the first trimester of gestation induced abortion between 60 and 72 hr in three cows. Plasma PGF2 alpha levels in the aborting cows increased significantly to 289% of the zero time control (ZTC) at 1 hr and remained elevated for 9 hr. The PGF2 alpha level remained unaffected in the non-aborting cows except at 2 hr. The plasma TxB2 levels were increased by 6 to 18 fold for 6 hr in both the aborting and non-aborting cows relative to their ZTC controls. The 6-keto-PGF1 alpha levels were significantly increased to 2 to 3 fold only in the aborting cows. Plasma cortisol levels were increased maximally to 1,500% of ZTC at 5 hr in the aborting cows. Thereafter, the levels gradually declined but remained significantly elevated for 24 hr. The increases in the cortisol levels in the non-aborting cows were only 280% of ZTC at 5 hr and returned to ZTC value by 12 hr. Plasma progesterone levels in the aborting cows remained unaffected until 12 hr followed by a progressive decline through 18 hr to extremely low levels at 3, 4, and 5 days. Endotoxin-infusion caused hyperglycemia in both aborting and non-aborting cows and lactic acidemia in the aborting cows. Treatment with two doses of flunixin meglumine (FM, 1.1 mg/kg), an inhibitor of cyclooxygenase, 1 hr prior to endotoxin infusion and then 13 hr later, completely prevented the endotoxin-induced abortion and increases in the plasma PGF2 alpha, TxB2 and 6-keto-PGF1 alpha concentrations. The PGE level remained unaffected. Although FM treatment failed to abolish endotoxin-induced increases in the plasma cortisol and lactic acid levels, it effectively prevented marked decreases in the progesterone and increases in the glucose concentrations. It was concluded that the use of FM offers therapeutic promise in preventing bovine abortion caused by endotoxin resulting from bacterial infection during the 1st trimester of gestation.

Endogenous bilirubin excretion in Bolivian squirrel monkeys with a Gilbert's-like syndrome.

Fasted Bolivian squirrel monkeys (BoSM) exhibit a marked hyperbilirubinemia when compared to fed BoSM. This fasting hyperbilirubinemia (FH) is similar to that in human patients with Gilbert's syndrome. Endogenous bilirubin (BR) excretion (production) into bile was elevated two-fold in BoSM upon fasting. The fraction of injected dose of 3 H-amino-levulinic acid (ALA) incorporated into biliary BR in fasted monkeys was of less magnitude than in fed monkeys and was associated with lower specific activities of 3 H-BR. Both the lower incorporation of ALA and lower specific activities of 3H-BR in fasted BoSM suggest that increased BR excreted may have arisen from pre-existing non-labeled pools of either heme or BR.

Kinetic properties of bilirubin UDP-glucuronyltransferase in squirrel monkeys exhibiting fasting hyperbilirubinemia.

1. Bolivian squirrel monkeys (BoSM), unlike Brazilian squirrel monkeys (BrSM), exhibit a marked fasting hyperbilirubinemia (FH) and serve as animal models for Gilbert's syndrome type I. 2. Compared to BrSM, BoSM possess a higher apparent UDPGAKm (0.51 vs 0.29 mM) and lower Vm (0.36 vs 0.48 nmol BR conjugated/min per mg microsomal protein) for hepatic bilirubin (BR) UDP-glucuronyl-transferase (BR UDPG-T). 3. Lineweaver-Burk plots are linear and obey Michaelis-Menten kinetics when UDP-acetylglucosamine is used as activator and UDPGA substrate concentrations are within the physiologic range present in the liver during the fed and fasted state (0.10-0.71 mM); above these concentrations, there is a discontinuity of kinetic plots as noted in other species. 4. There is no effect of fasting on the Km of BR conjugation (i.e. sum of mono- and diglucuronides) in either monkey; however, fasting is associated with lower Vm values (15-20%) in each subspecies. 5. By calculating the potential BR flux (nmol BR conjugated/min per kg) using known hepatic UDPGA concentrations, liver weights and in vitro Km and Vm, a markedly lower BR flux is observed in BoSM (58.4 nmol/min per kg) than in BrSM (91.6 nmol/min per kg). 6. Significantly higher apparent UDPGAKm and lower Vm of BR UDPG-T for conjugation of BR to BR monoglucuronide appears responsible in part for the four- to five-fold elevations in unconjugated BR in the liver and plasma in the fasted BoSM.

Effect of diseases, production, and season on traumatic reticuloperitonitis and ruminal acidosis in dairy cattle.

Logistic regression was used to investigate the effects of host characteristics, production, and 23 veterinary diagnoses on the risks of two reticuloruminal disorders, ruminal acidosis and traumatic reticuloperitonitis among 61,124 Finnish Ayrshire cows. Lactational incidence risks were .3% for ruminal acidosis and .6% for traumatic reticuloperitonitis. The relative risk of ruminal acidosis was not related to parity, whereas the risk of traumatic reticuloperitonitis decreased with increasing parity. The risk of traumatic reticuloperitonitis was not related to milk yield of individual affected cows in their current or previous lactation (305-d, 4% FCM), whereas the risk of ruminal acidosis increased with current milk yield. Ketosis, early metritis, nonparturient paresis, and acute and chronic mastitis were risk factors for both reticuloruminal disorders. Parturient paresis was a risk factor for ruminal acidosis. Foot and leg problems were risk factors for traumatic reticuloperitonitis. Herd milk yield in the current or previous lactations was not a risk factor for either disorder nor were the two disorders risk factors for each other. Ruminal acidosis, but not traumatic reticuloperitonitis, had significant seasonal variation with the risk being least in summer. The low risk of ruminal acidosis in summer was not due to seasonality of calving.

Partitioning of amino acids in lactating cows: oxidation to carbon dioxide.

The rate and extent of oxidation of 20 different amino acids has been evaluated as part of a study on partitioning of amino acids in normal lactating cows. Only four amino acids--glutamate, aspartate, alanine and glutamine--were extensively oxidized, and when expressed as a percentage of the injected dose oxidized during 3 h after intravenous injection, the value for these four amino acids was not significantly different from those obtained with the volatile fatty acids. The oxidation of all other amino acids was significantly slower, effectively prolonging their availability for protein synthesis. The pattern of oxidation among the amino acids supports the hypothesis that catabolized protein can provide a protracted source of anaplerotic precursors that augment the metabolic role of the tricarboxylic acid cycle and would have survival advantage in both acute and chronic exigencies. Glutamate and aspartate provide the earliest and largest influx to the tricarboxylic acid cycle, with alanine and, especially, glutamine appearing to serve as reservoirs of amino-nitrogen. Several dispensable amino acids are metabolized as slowly as the indispensable ones, indicating that metabolic conservation is not restricted to the latter group.

Methods for control of lamb epididymitis in large purebred flocks.

An autogenous, multivalent, adjuvanted bacterin for epididymitis was tested in flocks of 700 to 800 Suffolk X white-faced lambs. Long-term feeding of low dosages of antibiotics also was tested in the Suffolk flock. Both methods appeared to reduce the incidence of the disease. The incidence of clinical epididymitis and the number of positive culture results from clinically affected rams were significantly reduced.

Effects of endotoxin infusion on circulating levels of eicosanoids, progesterone, cortisol, glucose and lactic acid, and abortion in pregnant cows.

The effects of Escherichia coli endotoxin infusions (1.0 or 2.5 micrograms kg-1 over 6 h) on pregnancy were investigated in cows in the first, second and third trimester of gestation. Endotoxin increased the plasma levels of prostaglandins (PGs), thromboxane B2 and cortisol, and decreased progesterone. The severity of the clinical signs and the magnitude of the increases in plasma PGs, thromboxane B2 and cortisol tended to depend on the dose of endotoxin, but were independent of the gestation period. There was hyperglycemia followed by hypoglycemia and lactic acidemia. Hyperglycemia and lactic acidemia were significant only at the high dose of endotoxin. Endotoxin infusion at both doses caused a preferential mobilization of oleic acid from adipose tissue, and also had some effects on the mobilization of palmitic and stearic acids during the post-infusion period. The cows in the first trimester of gestation were more sensitive to the abortifacient effect of endotoxin than cows in the second and third trimester of gestation. The results of this study indicate that the mechanism of endotoxin-induced abortion in cows initially involves a prolonged release of PGF2 alpha and its subsequent stimulant effect on uterine smooth muscle contraction and luteolytic effect leading to a gradual decline in the plasma levels of progesterone. It was concluded that pregnancy terminates in the absence of an adequate level of progesterone, especially during the first trimester of gestation, when progesterone of extraluteal origin is not yet available, coupled with the PGF2 alpha-induced propulsive contraction of the uterus. In addition, the metabolic and circulatory failures in severe cases of endotoxemia, especially at the high dose of endotoxin, resulting either directly or indirectly via the release of various autacoids, catecholamines and cortisol, may also contribute to the termination of pregnancy at any stage of gestation.

Hepatic bilirubin and UDP-glucuronate levels in Bolivian squirrel monkeys exhibiting fasting hyperbilirubinemia.

1. Bolivian squirrel monkeys (BoSMs), which are animal models for Gilbert's syndrome, have 40% less hepatic bilirubin UDP-glucuronyltransferase (BR-UPPG-T) activity than Brazilian squirrel monkeys (BrSMs). 2. Although fasting results in similar decreases in hepatic UDP-glucose and UDP-glucuronate levels in both simian subspecies, increased activities (55%) of BR-UDPG-T are induced only in the fasted control BrSMs, which do not exhibit the marked fasting hyperbilirubinemia (FH). 3. Total hepatic bilirubin (BR) concentrations were 50% greater in both fed and fasted BoSMs when compared to BrSMs. 4. Hepatic unconjugated BR levels increase upon fasting only in Gilbert-like BoSMs, reaching concentrations twice that observed in BrSMs. 5. Elevated hepatic BR levels in fasted BoSMs may reflect BR overproduction or inadequate glucuronidation. 6. The increased BR-UDPG-T activity induced in BrSMs during fasting could compensate in-part for the UDPGA depletion and prevent the marked FH as observed in BoSMs.

Bilirubin excretion and bile flow in fed and fasted Brazilian squirrel monkeys (Saimiri sciureus).

Fasted Brazilian squirrel monkeys (BrSMs) exhibited slightly higher serum bilirubin levels (0.30 +/- 0.05 mg/dl) than others in the fed state (0.13 +/- 0.01). The mean liver weight was 50% lower following a 22 h fast. The rate of bile flow was unaffected by fasting and averaged 13.8 microliters/min/kg and 47.5 microliters/min/100g liver in six BrSMs. No significant difference in mean bilirubin excretion/min was observed on a body weight basis following fasting. When the mean rate of bilirubin excretion was calculated as a function of liver weight, a two-fold higher rate was present in fasted monkeys, but only at the p = 0.06 level of statistical significance. From data collected in this and earlier studies, it would appear that BrSMs represent the best animals studied to date to serve as experimental controls in comparative studies with Bolivian squirrel monkeys which exhibit a Gilbert-like syndrome.